TNKase

tenecteplase

Dosage Form: injection
TNKase®

(Tenecteplase)

TNKase Description

TNKase® (Tenecteplase) is a tissue plasminogen activator (tPA) produced by recombinant DNA technology using an established mammalian cell line (Chinese Hamster Ovary cells). Tenecteplase is a 527 amino acid glycoprotein developed by introducing the following modifications to the complementary DNA (cDNA) for natural human tPA: a substitution of threonine 103 with asparagine, and a substitution of asparagine 117 with glutamine, both within the kringle 1 domain, and a tetra-alanine substitution at amino acids 296–299 in the protease domain. Cell culture is carried out in nutrient medium containing the antibiotic gentamicin (65 mg/L). However, the presence of the antibiotic is not detectable in the final product (limit of detection is 0.67 µg/vial). TNKase is a sterile, white to off-white, lyophilized powder for single intravenous (IV) bolus administration after reconstitution with Sterile Water for Injection (SWFI), USP. Each vial of TNKase nominally contains 52.5 mg Tenecteplase, 0.55 g L-arginine, 0.17 g phosphoric acid, and 4.3 mg polysorbate 20, which includes a 5% overfill. Each vial will deliver 50 mg of Tenecteplase.

TNKase - Clinical Pharmacology

General

Tenecteplase is a modified form of human tissue plasminogen activator (tPA) that binds to fibrin and converts plasminogen to plasmin. In the presence of fibrin, in vitro studies demonstrate that Tenecteplase conversion of plasminogen to plasmin is increased relative to its conversion in the absence of fibrin. This fibrin specificity decreases systemic activation of plasminogen and the resulting degradation of circulating fibrinogen as compared to a molecule lacking this property. Following administration of 30, 40, or 50 mg of TNKase, there are decreases in circulating fibrinogen (4%–15%) and plasminogen (11%–24%). The clinical significance of fibrin-specificity on safety (e.g., bleeding) or efficacy has not been established. Biological potency is determined by an in vitro clot lysis assay and is expressed in Tenecteplase-specific units. The specific activity of Tenecteplase has been defined as 200 units/mg.

Pharmacokinetics

In patients with acute myocardial infarction (AMI), TNKase administered as a single bolus exhibits a biphasic disposition from the plasma. Tenecteplase was cleared from the plasma with an initial half-life of 20 to 24 minutes. The terminal phase half-life of Tenecteplase was 90 to 130 minutes. In 99 of 104 patients treated with Tenecteplase, mean plasma clearance ranged from 99 to 119 mL/min.

The initial volume of distribution is weight related and approximates plasma volume. Liver metabolism is the major clearance mechanism for Tenecteplase.

Clinical Studies

ASSENT-2 was an international, randomized, double-blind trial that compared 30-day mortality rates in 16,949 patients assigned to receive an IV bolus dose of TNKase or an accelerated infusion of Activase® (Alteplase).1 Eligibility criteria included onset of chest pain within 6 hours of randomization and ST-segment elevation or left bundle branch block on electrocardiogram (ECG). Patients were to be excluded from the trial if they received GP IIb/IIIa inhibitors within the previous 12 hours. TNKase was dosed using actual or estimated weight in a weight-tiered fashion as described in DOSAGE AND ADMINISTRATION. All patients were to receive 150–325 mg of aspirin administered as soon as possible, followed by 150–325 mg daily. Intravenous heparin was to be administered as soon as possible: for patients weighing ≤67 kg, heparin was administered as a 4000 unit IV bolus followed by infusion at 800 U/hr; for patients weighing >67 kg, heparin was administered as a 5000 unit IV bolus followed by infusion at 1000 U/hr. Heparin was continued for 48 to 72 hours with infusion adjusted to maintain aPTT at 50–75 seconds. The use of GP IIb/IIIa inhibitors was discouraged for the first 24 hours following randomization. The results of the primary endpoint (30-day mortality rates with non-parametric adjustment for the covariates of age, Killip class, heart rate, systolic blood pressure and infarct location) along with selected other 30-day endpoints are shown in Table 1.

Table 1 ASSENT-2 Mortality, Stroke, and Combined Outcome of Death or Stroke Measured at Thirty Days

30-Day Events	TNKase (n = 8461)	Accelerated Activase (n = 8488)	Relative Risk TNKase/Activase (95% CI)
Mortality	6.2%	6.2%	1.00 (0.89, 1.12)
Intracranial Hemorrhage (ICH)	0.9%	0.9%	0.99 (0.73, 1.35)
Any Stroke	1.8%	1.7%	1.07 (0.86, 1.35)
Death or Nonfatal Stroke	7.1%	7.0%	1.01 (0.91, 1.13)

Rates of mortality and the combined endpoint of death or stroke among pre-specified subgroups, including age, gender, time to treatment, infarct location, and history of previous myocardial infarction, demonstrate consistent relative risks across these subgroups. There was insufficient enrollment of non-Caucasian patients to draw any conclusions regarding relative efficacy in racial subsets.

Rates of in-hospital procedures, including percutaneous transluminal coronary angioplasty (PTCA), stent placement, intra-aortic balloon pump (IABP) use, and coronary artery bypass graft (CABG) surgery, were similar between the TNKase and Activase®(Alteplase) groups.

TIMI 10B was an open-label, controlled, randomized, dose-ranging, angiography study which utilized a blinded core laboratory for review of coronary arteriograms.2 Patients (n = 837) presenting within 12 hours of symptom onset were treated with fixed doses of 30, 40, or 50 mg of TNKase or the accelerated infusion of Activase and underwent coronary arteriography at 90 minutes. The results showed that the 40 mg and 50 mg doses were similar to accelerated infusion of Activase in restoring patency. TIMI Grade 3 flow and TIMI Grade 2/3 flow at 90 minutes are shown in Table 2. The exact relationship between coronary artery patency and clinical activity has not been established.

Table 2 TIMI 10B Patency Rates TIMI Grade Flow at 90 Minutes

	Activase ≤100 mg (n=311)	TNKase 30 mg (n=302)	TNKase 40 mg (n=148)	TNKase 50 mg (n=76)
TIMI Grade 3 Flow	63%	54%	63%	66%
TIMI Grade 2/3 Flow	82%	77%	79%	88%
95% CI (TIMI 2/3 Flow)	(77%,86%)	(72%,81%)	(72%,85%)	(79%,94%)

The angiographic results from TIMI 10B and the safety data from ASSENT-1, an additional uncontrolled safety study of 3,235 TNKase-treated patients, provided the framework to develop a weight-tiered TNKase dose regimen.3 Exploratory analyses suggested that a weight-adjusted dose of 0.5 mg/kg to 0.6 mg/kg of TNKase resulted in a better patency to bleeding relationship than fixed doses of TNKase across a broad range of patient weights.

The Assessment of the Safety and Efficacy of a New Treatment Strategy with Percutaneous Coronary Intervention (ASSENT 4 PCI) was a Phase IIIb/IV study designed to assess the safety and effectiveness of a strategy of administering full dose TNKase with a single bolus of 4000 U of unfractionated heparin in patients with ST segment elevation AMI, in whom primary percutaneous coronary intervention (PCI) was planned, but in whom a delay of 1–3 hours was anticipated before PCI. The trial was prematurely terminated with 1667 randomized patients (75 of whom were treated in the United States) due to a numerically higher mortality in the patients receiving TNKase prior to primary PCI versus PCI without TNKase (median time from randomization to balloon of 115 minutes). The incidence of the 90‑day primary endpoint, a composite of death or cardiogenic shock or congestive heart failure (CHF) within 90 days, was 18.6% in patients treated with TNKase plus PCI versus 13.4% in those treated with PCI alone (p=0.0055; OR 1.39 (95% C.I. 1.11–1.74)).

There were trends toward worse outcomes in the individual components of the primary endpoint between TNKase plus PCI versus PCI alone (mortality 6.7% vs. 5.0%, respectively; cardiogenic shock 6.1% vs. 4.8%, respectively; and CHF 12.1% vs. 9.4%, respectively). In addition, there were trends towards worse outcomes in recurrent MI (6.1% vs. 3.5%, respectively; p=0.03) and repeat target vessel revascularization (6.6% vs. 3.6%, respectively; p=0.005) in patients receiving TNKase plus PCI versus PCI alone.

There was no difference in in‑hospital major bleeding between the two groups (5.6% vs. 4.4% for TNKase plus PCI vs. PCI alone, respectively). For patients treated with TNKase plus PCI, in‑hospital rates of intracranial hemorrhage and total stroke were similar to those observed in previous trials (0.97% and 1.8%, respectively); however, none of the patients treated with PCI alone experienced a stroke (ischemic, hemorrhagic or other).

Indications and Usage for TNKase

TNKase® (Tenecteplase) is indicated for use in the reduction of mortality associated with acute myocardial infarction (AMI). Treatment should be initiated as soon as possible after the onset of AMI symptoms (see CLINICAL STUDIES).

Contraindications

TNKase therapy in patients with acute myocardial infarction is contraindicated in the following situations because of an increased risk of bleeding (see WARNINGS):

• Active internal bleeding


• History of cerebrovascular accident


• Intracranial or intraspinal surgery or trauma within 2 months


• Intracranial neoplasm, arteriovenous malformation, or aneurysm


• Known bleeding diathesis


• Severe uncontrolled hypertension

Warnings

Bleeding

The most common complication encountered during TNKase therapy is bleeding. The type of bleeding associated with thrombolytic therapy can be divided into two broad categories:

• Internal bleeding, involving intracranial and retroperitoneal sites, or the gastrointestinal, genitourinary, or respiratory tracts.


• Superficial or surface bleeding, observed mainly at vascular puncture and access sites (e.g., venous cutdowns, arterial punctures) or sites of recent surgical intervention.

Should serious bleeding (not controlled by local pressure) occur, any concomitant heparin or antiplatelet agents should be discontinued immediately.

In clinical studies of TNKase, patients were treated with both aspirin and heparin. Heparin may contribute to the bleeding risks associated with TNKase. The safety of the use of TNKase with other antiplatelet agents has not been adequately studied (see PRECAUTIONS: Drug Interactions). Intramuscular injections and nonessential handling of the patient should be avoided for the first few hours following treatment with TNKase. Venipunctures should be performed and monitored carefully.

Should an arterial puncture be necessary during the first few hours following TNKase therapy, it is preferable to use an upper extremity vessel that is accessible to manual compression. Pressure should be applied for at least 30 minutes, a pressure dressing applied, and the puncture site checked frequently for evidence of bleeding.

Each patient being considered for therapy with TNKase should be carefully evaluated and anticipated benefits weighed against potential risks associated with therapy. In the following conditions, the risk of TNKase therapy may be increased and should be weighed against the anticipated benefits:

• Recent major surgery, e.g., coronary artery bypass graft, obstetrical delivery, organ biopsy, previous puncture of noncompressible vessels


• Cerebrovascular disease


• Recent gastrointestinal or genitourinary bleeding


• Recent trauma


• Hypertension: systolic BP ≥180 mm Hg and/or diastolic BP ≥110 mm Hg


• High likelihood of left heart thrombus, e.g., mitral stenosis with atrial fibrillation


• Acute pericarditis


• Subacute bacterial endocarditis


• Hemostatic defects, including those secondary to severe hepatic or renal disease


• Severe hepatic dysfunction


• Pregnancy


• Diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions


• Septic thrombophlebitis or occluded AV cannula at seriously infected site


• Advanced age (see PRECAUTIONS: Geriatric Use)


• Patients currently receiving oral anticoagulants, e.g., warfarin sodium


• Recent administration of GP IIb/IIIa inhibitors


• Any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location

Cholesterol Embolization

Cholesterol embolism has been reported rarely in patients treated with all types of thrombolytic agents; the true incidence is unknown. This serious condition, which can be lethal, is also associated with invasive vascular procedures (e.g., cardiac catheterization, angiography, vascular surgery) and/or anticoagulant therapy. Clinical features of cholesterol embolism may include livedo reticularis, "purple toe" syndrome, acute renal failure, gangrenous digits, hypertension, pancreatitis, myocardial infarction, cerebral infarction, spinal cord infarction, retinal artery occlusion, bowel infarction, and rhabdomyolysis.

Arrhythmias

Coronary thrombolysis may result in arrhythmias associated with reperfusion. These arrhythmias (such as sinus bradycardia, accelerated idioventricular rhythm, ventricular premature depolarizations, ventricular tachycardia) are not different from those often seen in the ordinary course of acute myocardial infarction and may be managed with standard anti‑arrhythmic measures. It is recommended that anti‑arrhythmic therapy for bradycardia and/or ventricular irritability be available when TNKase is administered.

Use with Percutaneous Coronary Intervention (PCI)

In patients with large ST segment elevation myocardial infarction, physicians should choose either thrombolysis or PCI as the primary treatment strategy for reperfusion. Rescue PCI or subsequent elective PCI may be performed after administration of thrombolytic therapies if medically appropriate; however, the optimal use of adjunctive antithrombotic and antiplatelet therapies in this setting is unknown.

Precautions

General

Standard management of myocardial infarction should be implemented concomitantly with TNKase treatment. Arterial and venous punctures should be minimized. Noncompressible arterial puncture must be avoided and internal jugular and subclavian venous punctures should be avoided to minimize bleeding from the noncompressible sites. In the event of serious bleeding, heparin and antiplatelet agents should be discontinued immediately. Heparin effects can be reversed by protamine.

Readministration

Readministration of plasminogen activators, including TNKase, to patients who have received prior plasminogen activator therapy has not been systematically studied. Three of 487 patients tested for antibody formation to TNKase had a positive antibody titer at 30 days. The data reflect the percentage of patients whose test results were considered positive for antibodies to TNKase in a radioimmunoprecipitation assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to TNKase with the incidence of antibodies to other products may be misleading. Although sustained antibody formation in patients receiving one dose of TNKase has not been documented, readministration should be undertaken with caution. If an anaphylactic reaction occurs, appropriate therapy should be administered.

Drug Interactions

Formal interaction studies of TNKase with other drugs have not been performed. Patients studied in clinical trials of TNKase were routinely treated with heparin and aspirin. Anticoagulants (such as heparin and vitamin K antagonists) and drugs that alter platelet function (such as acetylsalicylic acid, dipyridamole, and GP IIb/IIIa inhibitors) may increase the risk of bleeding if administered prior to, during, or after TNKase therapy.

Drug/Laboratory Test Interactions

During TNKase therapy, results of coagulation tests and/or measures of fibrinolytic activity may be unreliable unless specific precautions are taken to prevent in vitro artifacts. Tenecteplase is an enzyme that, when present in blood in pharmacologic concentrations, remains active under in vitro conditions. This can lead to degradation of fibrinogen in blood samples removed for analysis.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies in animals have not been performed to evaluate the carcinogenic potential, mutagenicity, or the effect on fertility.

Pregnancy (Category C)

TNKase has been shown to elicit maternal and embryo toxicity in rabbits given multiple IV administrations. In rabbits administered 0.5, 1.5, and 5.0 mg/kg/day, vaginal hemorrhage resulted in maternal deaths. Subsequent embryonic deaths were secondary to maternal hemorrhage and no fetal anomalies were observed. TNKase does not elicit maternal and embryo toxicity in rabbits following a single IV administration. Thus, in developmental toxicity studies conducted in rabbits, the no observable effect level (NOEL) of a single IV administration of TNKase on maternal or developmental toxicity was 5 mg/kg (approximately 8–10 times the human dose). There are no adequate and well‑controlled studies in pregnant women. TNKase should be given to pregnant women only if the potential benefits justify the potential risk to the fetus.

Nursing Mothers

It is not known if TNKase is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TNKase is administered to a nursing woman.

Pediatric Use

The safety and effectiveness of TNKase in pediatric patients have not been established.

Geriatric Use

Of the patients in ASSENT-2 who received TNKase, 4,958 (59%) were under the age of 65; 2,256 (27%) were between the ages of 65 and 74; and 1,244 (15%) were 75 and over. The 30-day mortality rates by age were 2.5% in patients under the age of 65, 8.5% in patients between the ages of 65 and 74, and 16.2% in patients age 75 and over. The ICH rates were 0.4% in patients under the age of 65, 1.6% in patients between the ages of 65 and 74, and 1.7% in patients age 75 and over. The rates of any stroke were 1.0% in patients under the age of 65, 2.9% in patients between the ages of 65 and 74, and 3.0% in patients age 75 and over. Major bleeding rates, defined as bleeding requiring blood transfusion or leading to hemodynamic compromise, were 3.1% in patients under the age of 65, 6.4% in patients between the ages of 65 and 74, and 7.7% in patients age 75 and over. In elderly patients, the benefits of TNKase on mortality should be carefully weighed against the risk of increased adverse events, including bleeding.

Adverse Reactions

Bleeding

The most frequent adverse reaction associated with TNKase is bleeding (see WARNINGS).

Should serious bleeding occur, concomitant heparin and antiplatelet therapy should be discontinued. Death or permanent disability can occur in patients who experience stroke or serious bleeding episodes.

For TNKase-treated patients in ASSENT-2, the incidence of intracranial hemorrhage was 0.9% and any stroke was 1.8%. The incidence of all strokes, including intracranial bleeding, increases with increasing age (see PRECAUTIONS: Geriatric Use).

In the ASSENT-2 study, the following bleeding events were reported (see Table 3).

Table 3 ASSENT-2 Non-ICH Bleeding Events

	TNKase (n = 8461)	Accelerated Activase (n = 8488)	Relative Risk for TNKase/Activase (95% CI)
* Major bleeding is defined as bleeding requiring blood transfusion or leading to hemodynamic compromise.
Major bleeding*	4.7%	5.9%	0.78 (0.69, 0.89)
Minor bleeding	21.8%	23.0%	0.94 (0.89, 1.00)
Units of transfused blood
Any	4.3%	5.5%	0.77 (0.67, 0.89)
1–2	2.6%	3.2%
>2	1.7%	2.2%

Non-intracranial major bleeding and the need for blood transfusions were lower in patients treated with TNKase.

Types of major bleeding reported in 1% or more of the patients were hematoma (1.7%) and gastrointestinal tract (1%). Types of major bleeding reported in less than 1% of the patients were urinary tract, puncture site (including cardiac catheterization site), retroperitoneal, respiratory tract, and unspecified. Types of minor bleeding reported in 1% or more of the patients were hematoma (12.3%), urinary tract (3.7%), puncture site (including cardiac catheterization site) (3.6%), pharyngeal (3.1%), gastrointestinal tract (1.9%), epistaxis (1.5%), and unspecified (1.3%).

Allergic Reactions

Allergic-type reactions (e.g., anaphylaxis, angioedema, laryngeal edema, rash, and urticaria) have rarely (< 1%) been reported in patients treated with TNKase. Anaphylaxis was reported in < 0.1% of patients treated with TNKase; however, causality was not established. When such reactions occur, they usually respond to conventional therapy.

Other Adverse Reactions

The following adverse reactions have been reported among patients receiving TNKase in clinical trials. These reactions are frequent sequelae of the underlying disease, and the effect of TNKase on the incidence of these events is unknown.

These events include cardiogenic shock, arrhythmias, atrioventricular block, pulmonary edema, heart failure, cardiac arrest, recurrent myocardial ischemia, myocardial reinfarction, myocardial rupture, cardiac tamponade, pericarditis, pericardial effusion, mitral regurgitation, thrombosis, embolism, and electromechanical dissociation. These events can be life-threatening and may lead to death. Nausea and/or vomiting, hypotension, and fever have also been reported.

TNKase Dosage and Administration

Dosage

TNKase® (Tenecteplase) is for intravenous administration only. The recommended total dose should not exceed 50 mg and is based upon patient weight.

A single bolus dose should be administered over 5 seconds based on patient weight. Treatment should be initiated as soon as possible after the onset of AMI symptoms (see CLINICAL STUDIES).

Dose Information Table

Patient Weight (kg)	TNKase (mg)	Volume TNKase* to be administered (mL)
* From one vial of TNKase reconstituted with 10 mL SWFI.
<60	30	6
≥60 to <70	35	7
≥70 to <80	40	8
≥80 to <90	45	9
≥90	50	10

The safety and efficacy of TNKase have only been investigated with concomitant administration of heparin and aspirin as described in CLINICAL STUDIES.

THE

Reconstitution

NOTE: Read all instructions completely before beginning reconstitution and administration.

1. 
   

   Remove the shield assembly from the supplied B-D® 10 mL syringe with TwinPak™ Dual Cannula Device (see figure) and aseptically withdraw 10 mL of Sterile Water for Injection (SWFI), USP, from the supplied diluent vial using the red hub cannula syringe filling device. Do not use Bacteriostatic Water for Injection, USP.

   
   

   Note: Do not discard the shield assembly.

   
   


2. Inject the entire contents of the syringe (10 mL) into the TNKase vial directing the diluent stream into the powder. Slight foaming upon reconstitution is not unusual; any large bubbles will dissipate if the product is allowed to stand undisturbed for several minutes.


3. Gently swirl until contents are completely dissolved. DO NOT SHAKE. The reconstituted preparation results in a colorless to pale yellow transparent solution containing TNKase at 5 mg/mL at a pH of approximately 7.3. The osmolality of this solution is approximately 290 mOsm/kg.


4. Determine the appropriate dose of TNKase (see Dose Information Table) and withdraw this volume (in milliliters) from the reconstituted vial with the syringe. Any unused solution should be discarded.


5. Once the appropriate dose of TNKase is drawn into the syringe, stand the shield vertically on a flat surface (with green side down) and passively recap the red hub cannula.


6. Remove the entire shield assembly, including the red hub cannula, by twisting counterclockwise. Note: The shield assembly also contains the clear-ended blunt plastic cannula; retain for split septum IV access.

Administration

1.

The product should be visually inspected prior to administration for particulate matter and discoloration. TNKase may be administered as reconstituted at 5 mg/mL.

2.

Precipitation may occur when TNKase is administered in an IV line containing dextrose. Dextrose-containing lines should be flushed with a saline-containing solution prior to and following single bolus administration of TNKase.

3.

Reconstituted TNKase should be administered as a single IV bolus over 5 seconds.

4.

Because TNKase contains no antibacterial preservatives, it should be reconstituted immediately before use. If the reconstituted TNKase is not used immediately, refrigerate the TNKase vial at 2–8°C (36–46°F) and use within 8 hours.

5.

Although the supplied syringe is compatible with a conventional needle, this syringe is designed to be used with needleless IV systems. From the information below, follow the instructions applicable to the IV system in use.

Split septum IV system:	Remove the green cap. Attach the clear-ended blunt plastic cannula to the syringe. Remove the shield and use the blunt plastic cannula to access the split septum injection port. Because the blunt plastic cannula has two side ports, air or fluid expelled through the cannula will exit in two sideways directions; direct away from face or mucous membranes.
Luer-Lok® system:	Connect syringe directly to IV port.
Conventional needle (not supplied in this kit):	Attach a large bore needle, e.g., 18 gauge, to the syringe's universal Luer‑Lok®.

6.

Dispose of the syringe, cannula and shield per established procedures.

How is TNKase Supplied

TNKase® (Tenecteplase) is supplied as a sterile, lyophilized powder in a 50 mg vial under partial vacuum. Each 50 mg vial of TNKase is packaged with one 10 mL vial of Sterile Water for Injection, USP for reconstitution, the B-D® 10 mL syringe with TwinPak™ Dual Cannula Device, and three alcohol prep pads. NDC 50242-120-01.

Stability and Storage

Store lyophilized TNKase at controlled room temperature not to exceed 30°C (86°F) or under refrigeration 2–8°C (36–46°F). Do not use beyond the expiration date stamped on the vial.

REFERENCES

1. ASSENT-2 Investigators. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial. Lancet1999;354:716-22.


2. Cannon CP, Gibson CM, McCabe CH, Adgey AAJ, Schweiger MJ, Sequeira RF, et al. TNK-tissue plasminogen activator compared with front-loaded alteplase in acute myocardial infarction. Results of the TIMI 10B trial. Circulation1998;98:2805–14.


3. Van de Werf F, Cannon CP, Luyten A, Houbracken K, McCabe CH, Berioli S, et al. Safety assessment of a single bolus administration of TNK tissue- plasminogen activator in acute myocardial infarction: the ASSENT-1 trial. Am Heart J1999;137:786–91.

TNKase® [Tenecteplase]
Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990	4851700 Initial US Approval June 2000 Revision Date May 2011 TNKase is a registered Trademark of Genentech, Inc. ©2011 Genentech, Inc.

TNKase 50mg Principal Display Panel

TNKase  tenecteplase  kit

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 50242-120

Packaging # NDC Package Description Multilevel Packaging 1 50242-120-01 1 KIT In 1 CARTON None

QUANTITY OF PARTS Part # Package Quantity Total Product Quantity Part 1 1 VIAL, SINGLE-USE   50 mg Part 2 1 VIAL, SINGLE-USE   10 mL

Part 1 of 2 TNKase  tenecteplase  injection, solution

Product Information       Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Tenecteplase (tenecteplase) Tenecteplase 52.5 mg  in 50 mg

Inactive Ingredients Ingredient Name Strength Arginine 0.55 g  in 50 mg Phosphoric Acid 0.17 g  in 50 mg Polysorbate 20 4.3 mg  in 50 mg

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 50 mg In 1 VIAL, SINGLE-USE None

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA103909

Part 2 of 2 STERILE WATER  water  injection

Product Information       Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength No Active Ingredients Found

Inactive Ingredients Ingredient Name Strength Water

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 10 mL In 1 VIAL, SINGLE-USE None

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA103909

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
BLA	BLA103909	06/02/2000

Labeler - Genentech, Inc. (080129000)

Registrant - Genentech, Inc. (080129000)

Establishment
Name	Address	ID/FEI	Operations
Genentech, Inc. (SSF)		080129000	MANUFACTURE, API MANUFACTURE, ANALYSIS

Revised: 08/2011Genentech, Inc.

More TNKase resources

• TNKase Side Effects (in more detail)
• TNKase Use in Pregnancy & Breastfeeding
• TNKase Drug Interactions
• TNKase Support Group
• 0 Reviews for TNKase - Add your own review/rating

• TNKase Concise Consumer Information (Cerner Multum)


• TNKase Monograph (AHFS DI)


• Tnkase Advanced Consumer (Micromedex) - Includes Dosage Information

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Keralyt Scalp Topical

Generic Name: salicylic acid (Topical route)

sal-i-SIL-ik AS-id

Commonly used brand name(s)

In the U.S.

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Available Dosage Forms:

• Soap


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Therapeutic Class: Antiacne

Pharmacologic Class: NSAID

Chemical Class: Salicylate, Non-Aspirin

Uses For Keralyt Scalp

Salicylic acid is used to treat many skin disorders, such as acne, dandruff, psoriasis, seborrheic dermatitis of the skin and scalp, calluses, corns, common warts, and plantar warts, depending on the dosage form and strength of the preparation.

Some of these preparations are available only with your doctor's prescription.

Before Using Keralyt Scalp

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Young children may be at increased risk of unwanted effects because of increased absorption of salicylic acid through the skin. Also, young children may be more likely to get skin irritation from salicylic acid. Salicylic acid should not be applied to large areas of the body, used for long periods of time, or used under occlusive dressing (air-tight covering, such as kitchen plastic wrap) in infants and children. Salicylic acid should not be used in children younger than 2 years of age.

Geriatric

Elderly people are more likely to have age-related blood vessel disease. This may increase the chance of problems during treatment with this medicine.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Abciximab


• Argatroban


• Bivalirudin


• Cilostazol


• Citalopram


• Clovoxamine


• Dabigatran Etexilate


• Dipyridamole


• Escitalopram


• Femoxetine


• Flesinoxan


• Fluoxetine


• Fluvoxamine


• Fondaparinux


• Heparin


• Lepirudin


• Nefazodone


• Paroxetine


• Protein C


• Rivaroxaban


• Sertraline


• Sibutramine


• Ticlopidine


• Tirofiban


• Vilazodone


• Zimeldine

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acenocoumarol


• Anisindione


• Ardeparin


• Azilsartan Medoxomil


• Azosemide


• Bemetizide


• Bendroflumethiazide


• Benzthiazide


• Bumetanide


• Buthiazide


• Candesartan Cilexetil


• Certoparin


• Chlorothiazide


• Chlorthalidone


• Clopamide


• Cyclopenthiazide


• Dalteparin


• Danaparoid


• Dicumarol


• Enoxaparin


• Eprosartan


• Ethacrynic Acid


• Furosemide


• Hydrochlorothiazide


• Hydroflumethiazide


• Indapamide


• Irbesartan


• Losartan


• Methyclothiazide


• Metolazone


• Nadroparin


• Olmesartan Medoxomil


• Parnaparin


• Phenindione


• Phenprocoumon


• Piretanide


• Polythiazide


• Probenecid


• Reviparin


• Tamarind


• Tasosartan


• Telmisartan


• Tinzaparin


• Torsemide


• Trichlormethiazide


• Valsartan


• Warfarin


• Xipamide

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Blood vessel disease

• Diabetes mellitus (sugar diabetes)—Use of this medicine may cause severe redness or ulceration, especially on the hands or feet

• Inflammation, irritation, or infection of the skin—Use of this medicine may cause severe irritation if applied to inflamed, irritated, or infected area of the skin

• Influenza (flu) or


• Varicella (chicken pox)—This medicine should not be used in children and teenagers with the flu or chicken pox. There is a risk of Reye's syndrome.

• Kidney disease or


• Liver disease—Using this medicine for a long time over large areas could result in unwanted effects

Proper Use of salicylic acid

This section provides information on the proper use of a number of products that contain salicylic acid. It may not be specific to Keralyt Scalp. Please read with care.

It is very important that you use this medicine only as directed. Do not use more of it, do not use it more often, and do not use it for a longer time than recommended on the label, unless otherwise directed by your doctor. To do so may increase the chance of absorption through the skin and the chance of salicylic acid poisoning.

If your doctor has ordered an occlusive dressing (airtight covering, such as kitchen plastic wrap) to be applied over this medicine, make sure you know how to apply it. Since an occlusive dressing will increase the amount of medicine absorbed through your skin and the possibility of salicylic acid poisoning, use it only as directed. If you have any questions about this, check with your doctor.

Keep this medicine away from the eyes and other mucous membranes, such as the mouth and inside of the nose. If you should accidentally get some in your eyes or on other mucous membranes, immediately flush them with water for 15 minutes.

To use the cream, lotion, or ointment form of salicylic acid:

• Apply enough medicine to cover the affected area, and rub in gently.

To use the gel form of salicylic acid:

• Before using salicylic acid gel, apply wet packs to the affected areas for at least 5 minutes. If you have any questions about this, check with your health care professional.


• Apply enough gel to cover the affected areas, and rub in gently.

To use the pad form of salicylic acid:

• Wipe the pad over the affected areas.


• Do not rinse off medicine after treatment.

To use the plaster form of salicylic acid for warts, corns, or calluses:

• This medicine comes with patient instructions. Read them carefully before using.


• Do not use this medicine on irritated skin or on any area that is infected or reddened. Also, do not use this medicine if you are a diabetic or if you have poor blood circulation.


• Do not use this medicine on warts with hair growing from them or on warts on the face, in or on the genital (sex) organs, or inside the nose or mouth. Also do not use on moles or birthmarks. To do so may cause severe irritation.


• Wash the area to be treated and dry thoroughly. Warts may be soaked in warm water for 5 minutes before drying.


• Cut the plaster to fit the wart, corn, or callus and apply.


• For corns and calluses:
  
  • Repeat every 48 hours as needed for up to 14 days, or as directed by your doctor, until the corn or callus is removed.
  
  
  • Corns or calluses may be soaked in warm water for 5 minutes to help in their removal.
  
  


• For warts:
  
  • Depending on the product, either:
    
    • Apply plaster and repeat every 48 hours as needed, or
      
      • Apply plaster at bedtime, leave in place for at least 8 hours, remove plaster in the morning, and repeat every 24 hours as needed.
      
      
    
    
  
  
  • Repeat for up to 12 weeks as needed, or as directed by your doctor, until wart is removed.
  
  


• If discomfort gets worse during treatment or continues after treatment, or if the wart spreads, check with your doctor.

To use the shampoo form of salicylic acid:

• Before applying this medicine, wet the hair and scalp with lukewarm water. Apply enough medicine to work up a lather and rub well into the scalp for 2 or 3 minutes, then rinse. Apply the medicine again and rinse thoroughly.

To use the soap form of salicylic acid:

• Work up a lather with the soap, using hot water, and scrub the entire affected area with a washcloth or facial sponge or mitt.


• If you are to use this soap in a foot bath, work up rich suds in hot water and soak the feet for 10 to 15 minutes. Then pat dry without rinsing.

To use the topical solution form of salicylic acid for acne:

• Wet a cotton ball or pad with the topical solution and wipe the affected areas.


• Do not rinse off medicine after treatment.

To use the topical solution form of salicylic acid for warts, corns, or calluses:

• This medicine comes with patient instructions. Read them carefully before using.


• This medicine is flammable. Do not use it near heat or open flame or while smoking.


• Do not use this medicine on irritated skin or on any area that is infected or reddened. Also, do not use this medicine if you are a diabetic or if you have poor blood circulation.


• Do not use this medicine on warts with hair growing from them or on warts on the face, in or on the genital (sex) organs, or inside the nose or mouth. Also do not use on moles or birthmarks. To do so may cause severe irritation.


• Avoid breathing in the vapors from the medicine.


• Wash the area to be treated and dry thoroughly. Warts may be soaked in warm water for 5 minutes before drying.


• Apply the medicine one drop at a time to completely cover each wart, corn, or callus. Let dry.


• For warts—Repeat one or two times a day as needed for up to 12 weeks, or as directed by your doctor, until wart is removed.


• For corns and calluses—Repeat one or two times a day as needed for up to 14 days, or as directed by your doctor, until the corn or callus is removed.


• Corns and calluses may be soaked in warm water for 5 minutes to help in their removal.


• If discomfort gets worse during treatment or continues after treatment, or if the wart spreads, check with your doctor.

Unless your hands are being treated, wash them immediately after applying this medicine to remove any medicine that may be on them.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For cream dosage form:
  
  • For corns and calluses:
    
    • Adults and children—Use the 2 to 10% cream as needed. Use the 25 to 60% cream one time every three to five days.
    
    
  
  


• For gel dosage form:
  
  • For acne:
    
    • Adults and children—Use the 0.5 to 5% gel one time a day.
    
    
  
  
  • For psoriasis:
    
    • Adults and children—Use the 5% gel one time a day.
    
    
  
  
  • For common warts:
    
    • Adults and children—Use the 5 to 26% gel one time a day.
    
    
  
  


• For lotion dosage form:
  
  • For acne:
    
    • Adults and children—Use the 1 to 2% lotion one to three times a day.
    
    
  
  
  • For dandruff and antiseborrhic dermatitis of the scalp:
    
    • Adults and children—Use the 1.8 to 2% lotion on the scalp one or two times a day.
    
    
  
  


• For ointment dosage form:
  
  • For acne:
    
    • Adults and children—Use the 3 to 6% ointment as needed.
    
    
  
  
  • For psoriasis and seborrheic dermatitis:
    
    • Adults and children—Use the 3 to 10% ointment as needed.
    
    
  
  
  • For common warts:
    
    • Adults and children—Use the 3 to 10% ointment as needed. Use the 25 to 60% ointment one time every three to five days.
    
    
  
  


• For pads dosage form:
  
  • For acne:
    
    • Adults and children—Use one to three times a day.
    
    
  
  


• For plaster dosage form:
  
  • For corns, calluses, common warts, or plantar warts:
    
    • Adults and children—Use one time a day or one time every other day.
    
    
  
  


• For shampoo dosage form:
  
  • For dandruff or seborrheic dermatitis of the scalp:
    
    • Adults and children—Use on the scalp one or two times a week.
    
    
  
  


• For soap dosage form:
  
  • For acne:
    
    • Adults and children—Use as needed.
    
    
  
  


• For topical solution dosage form:
  
  • For acne:
    
    • Adults and children—Use the 0.5 to 2% topical solution one to three times a day.
    
    
  
  
  • For common warts and plantar warts:
    
    • Adults and children—Use the 5 to 27% topical solution one or two times a day.
    
    
  
  
  • For corns and calluses:
    
    • Adults and children—Use the 12 to 27% topical solution one or two times a day.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, apply it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Precautions While Using Keralyt Scalp

When using salicylic acid, do not use any of the following preparations on the same affected area as this medicine, unless otherwise directed by your doctor:

• Abrasive soaps or cleansers


• Alcohol-containing preparations


• Any other topical acne preparation or preparation containing a peeling agent (for example, benzoyl peroxide, resorcinol, sulfur, or tretinoin [vitamin A acid])


• Cosmetics or soaps that dry the skin


• Medicated cosmetics


• Other topical medicine for the skin

To use any of the above preparations on the same affected area as salicylic acid may cause severe irritation of the skin.

Check with your doctor right away if you have nausea, vomiting, dizziness, loss of hearing, tinnitus, lethargy hyperpnea, diarrhea, and psychic disturbances. These could be symptoms of a serious condition called salicylate toxicity, especially in children under 12 years of age and patients with kidney or liver problems.

Keralyt Scalp Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor as soon as possible if any of the following side effects occur:

Less common or rare

• Skin irritation not present before use of this medicine (moderate or severe)

Frequency not known

• Dryness and peeling of skin


• flushing


• redness of skin


• unusually warm skin

Symptoms of salicylic acid poisoning

• Confusion


• diarrhea


• dizziness


• fast or deep breathing


• headache (severe or continuing)


• hearing loss


• lightheadedness


• nausea


• rapid breathing


• ringing or buzzing in ears (continuing)


• severe drowsiness


• stomach pain


• vomiting

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Skin irritation not present before use of this medicine (mild)


• stinging

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Keralyt Scalp Topical side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Keralyt Scalp Topical resources

• Keralyt Scalp Topical Side Effects (in more detail)
• Keralyt Scalp Topical Use in Pregnancy & Breastfeeding
• Keralyt Scalp Topical Drug Interactions
• Keralyt Scalp Topical Support Group
• 0 Reviews for Keralyt Scalp Topical - Add your own review/rating

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• Acne
• Dermatological Disorders
• Warts

Synercid

quinupristin and dalfopristin

Dosage Form: injection, powder, lyophilized, for solution
Synercid® I.V.

(quinupristin and dalfopristin for injection)

DESCRIPTION

Synercid® (quinupristin and dalfopristin powder for injection) I.V., a streptogramin antibacterial agent for intravenous administration, is a sterile lyophilized formulation of two semisynthetic pristinamycin derivatives, quinupristin (derived from pristinamycin I) and dalfopristin (derived from pristinamycin IIA) in the ratio of 30:70 (w/w).

Quinupristin is a white to very slightly yellow, hygroscopic powder. It is a combination of three peptide macrolactones. The main component of quinupristin (>88.0%) has the following chemical name: N-[(6R,9S,10R,13S,15aS,18R,22S,24aS ) - 22 - [p - (dimethylamino)benzyl] - 6 - ethyldocosahydro - 10,23 - dimethyl - 5,8,12,15,17,21,24 - heptaoxo - 13 - phenyl - 18 - [[(3S )-3-quinuclidinylthio] methyl]-12H-pyrido[2,1-f ]pyrrolo-[2,1-l ][1,4,7,10,13,16] oxapentaazacyclononadecin-9-yl]-3-hydroxypicolinamide.

The main component of quinupristin has an empirical formula of C53H67N9O10S, a molecular weight of 1022.24 and the following structural formula:

Dalfopristin is a slightly yellow to yellow, hygroscopic, powder. The chemical name for dalfopristin is: (3R,4R,5E,10E,12E,14S,26R,26aS ) - 26 - [[2 - (diethylamino)ethyl]sulfonyl] - 8,9,14,15,24,25,26,26a - octahydro - 14 - hydroxy - 3 - isopropyl - 4,12 - dimethyl - 3H - 21,18 - nitrilo - 1H,22H - pyrrolo[2,1 - c ][1,8,4,19]-dioxadiazacyclotetracosine-1,7,16,22(4H,17H )-tetrone.

Dalfopristin has an empirical formula of C34H50N4O9S, a molecular weight of 690.85 and the following structural formula:

CLINICAL PHARMACOLOGY

Pharmacokinetics

Quinupristin and dalfopristin are the main active components circulating in plasma in human subjects. Quinupristin and dalfopristin are converted to several active major metabolites: two conjugated metabolites for quinupristin (one with glutathione and one with cysteine) and one non-conjugated metabolite for dalfopristin (formed by drug hydrolysis).

Pharmacokinetic profiles of quinupristin and dalfopristin in combination with their metabolites were determined using a bioassay following multiple 60-minute infusions of Synercid in two groups of healthy young adult male volunteers. Each group received 7.5 mg/kg of Synercid intravenously q12h or q8h for a total of 9 or 10 doses, respectively. The pharmacokinetic parameters were proportional with q12h and q8h dosing; those of the q8h regimen are shown in the following table:

Mean Steady-State Pharmacokinetic Parameters of Quinupristin and Dalfopristin in Combination with their Metabolites (± SD1) (dose = 7.5 mg/kg q8h; n=10)

	Cmax2 (μg/mL)	AUC3 (μg.h/mL)	t 1/24 (hr)
1 SD= Standard Deviation
2 Cmax = Maximum drug plasma concentration
3 AUC = Area under the drug plasma concentration-time curve
4 t 1/2 = Half-life
Quinupristin and metabolites	3.20 ± 0.67	7.20 ± 1.24	3.07 ± 0.51
Dalfopristin and metabolite	7.96 ± 1.30	10.57 ± 2.24	1.04 ± 0.20

The clearances of unchanged quinupristin and dalfopristin are similar (0.72 L/h/kg), and the steady-state volume of distribution for quinupristin is 0.45 L/kg and for dalfopristin is 0.24 L/kg. The elimination half-life of quinupristin and dalfopristin is approximately 0.85 and 0.70 hours, respectively.

The total protein binding of quinupristin is higher than that of dalfopristin. Synercid does not alter the in vitro binding of warfarin to proteins in human serum.

Penetration of unchanged quinupristin and dalfopristin in noninflammatory blister fluid corresponds to about 19% and 11% of that estimated in plasma, respectively. The penetration into blister fluid of quinupristin and dalfopristin in combination with their major metabolites was in total approximately 40% compared to that in plasma.

In vitro, the transformation of the parent drugs into their major active metabolites occurs by non-enzymatic reactions and is not dependent on cytochrome-P450 or glutathione-transferase enzyme activities.

Synercid has been shown to be a major inhibitor (in vitro inhibits 70% cyclosporin A biotransformation at 10 μg/mL of Synercid) of the activity of cytochrome P450 3A4 isoenzyme. (See WARNINGS.)

Synercid can interfere with the metabolism of other drug products that are associated with QTc prolongation. However, electrophysiologic studies confirm that Synercid does not itself induce QTc prolongation. (See WARNINGS.)

Fecal excretion constitutes the main elimination route for both parent drugs and their metabolites (75 to 77% of dose). Urinary excretion accounts for approximately 15% of the quinupristin and 19% of the dalfopristin dose. Preclinical data in rats have demonstrated that approximately 80% of the dose is excreted in the bile and suggest that in man, biliary excretion is probably the principal route for fecal elimination.

Special Populations

Elderly: The pharmacokinetics of quinupristin and dalfopristin were studied in a population of elderly individuals (range 69 to 74 years). The pharmacokinetics of the drug products were not modified in these subjects.

Gender: The pharmacokinetics of quinupristin and dalfopristin are not modified by gender.

Renal Insufficiency: In patients with creatinine clearance 6 to 28 mL/min, the AUC of quinupristin and dalfopristin in combination with their major metabolites increased about 40% and 30%, respectively.

In patients undergoing Continuous Ambulatory Peritoneal Dialysis, dialysis clearance for quinupristin, dalfopristin and their metabolites is negligible. The plasma AUC of unchanged quinupristin and dalfopristin increased about 20% and 30%, respectively. The high molecular weight of both components of Synercid suggests that it is unlikely to be removed by hemodialysis.

Hepatic Insufficiency: In patients with hepatic dysfunction (Child-Pugh scores A and B), the terminal half-life of quinupristin and dalfopristin was not modified. However, the AUC of quinupristin and dalfopristin in combination with their major metabolites increased about 180% and 50%, respectively. (See DOSAGE AND ADMINISTRATION and PRECAUTIONS.)

Obesity (body mass index ≥30): In obese patients the Cmax and AUC of quinupristin increased about 30% and those of dalfopristin about 40%.

Pediatric Patients: The pharmacokinetics of Synercid in patients less than 16 years of age have not been studied.

Microbiology

The streptogramin components of Synercid, quinupristin and dalfopristin, are present in a ratio of 30 parts quinupristin to 70 parts dalfopristin. These two components act synergistically so that Synercid's microbiologic in vitro activity is greater than that of the components individually. Quinupristin's and dalfopristin's metabolites also contribute to the antimicrobial activity of Synercid. In vitro synergism of the major metabolites with the complementary parent compound has been demonstrated.

Mechanism of Action

The site of action of quinupristin and dalfopristin is the bacterial ribosome. Dalfopristin has been shown to inhibit the early phase of protein synthesis while quinupristin inhibits the late phase of protein synthesis. Synercid is bactericidal against isolates of methicillin-susceptible and methicillin-resistant staphylococci. The mode of action of Synercid differs from that of other classes of antibacterial agents such as ß-lactams, aminoglycosides, glycopeptides, quinolones, macrolides, lincosamides and tetracyclines. Therefore, there is no cross resistance between Synercid and these agents when tested by the minimum inhibitory concentration (MIC) method.

Mechanism of Resistance

Resistance to Synercid is associated with resistance to both components (i.e., quinupristin and dalfopristin). In non-comparative studies, emerging resistance to Synercid has occurred.

Interaction with other Antibacterials

In vitro combination testing of Synercid with aztreonam, cefotaxime, ciprofloxacin, and gentamicin against Enterobacteriaceae and Pseudomonas aeruginosa did not show antagonism.

In vitro combination testing of Synercid with prototype drugs of the following classes: aminoglycosides (gentamicin), β-lactams (cefepime, ampicillin, and amoxicillin), glycopeptides (vancomycin), quinolones (ciprofloxacin), tetracyclines (doxycycline) and also chloramphenicol against enterococci and staphylococci did not show antagonism.

Synercid has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections, as described in the INDICATIONS AND USAGE section.

Gram-positive bacteria

Staphylococcus aureus (methicillin-susceptible isolates only)

Streptococcus pyogenes

The following in vitro data are available, but their clinical significance is unknown.

The combination of quinupristin and dalfopristin (Synercid) exhibits in vitro minimum inhibitory concentrations (MIC's) of ≤1.0 μg/mL against most (≥90%) isolates of the following microorganisms; however, the safety and effectiveness of Synercid in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.

Gram-positive bacteria

Corynebacterium jeikeium

Staphylococcus aureus (methicillin-resistant isolates)

Staphylococcus epidermidis (including methicillin-resistant isolates)

Streptococcus agalactiae

SUSCEPTIBILITY TEST METHODS

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution1 method (broth or agar) or equivalent using standardized inoculum concentrations, and standardized concentrations of quinupristin/dalfopristin (Synercid) in a 30:70 ratio made from powder of known potency. The MIC values are interpreted according to the following criteria:

For Susceptibility Testing of Staphylococcus spp., and Streptococcus spp. (excluding Streptococcus pneumoniae)a.

MIC (μg/mL)	Interpretation
a.The interpretive values for Streptococcus spp. are applicable only to broth microdilution susceptibility testing using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood.
≤1.0	Susceptible (S)
2.0	Intermediate (I)
≥4.0	Resistant (R)

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the concentration of the antimicrobial compound in the blood reaches usually achievable levels. A report of “Intermediate” indicates that the result should be considered equivocal, and if the bacterium is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Quality Control

A standardized susceptibility test procedure requires the use of laboratory control bacteria to control the technical aspects of the laboratory procedures. Standard quinupristin/dalfopristin powder in a 30:70 ratio should provide the following MIC values with the indicated quality control strains:

Microorganisms (ATCC ®  #)	MIC (μg/mL)
Staphylococcus aureus (29213)	0.25 to 1.0

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 15 μg quinupristin/dalfopristin in a ratio of 30:70 (Synercid) to test the susceptibility of bacteria to quinupristin/dalfopristin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 15 μg quinupristin/dalfopristin disk are interpreted according to the following criteria:

For Susceptibility Testing of Staphylococcus spp., and Streptococcus spp. (excluding Streptococcus pneumoniae)b.

Zone Diameter (mm)	Interpretation
b.The zone diameter for Streptococcus spp. are applicable only to tests performed using Mueller-Hinton agar supplemented with 5% sheep blood when incubated in 5% CO2.
≥19	Susceptible (S)
16 to 18	Intermediate (I)
≤15	Resistant (R)

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for quinupristin/dalfopristin.

Quality Control

As with standardized dilution techniques, diffusion methods require the use of laboratory control bacteria that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 15 μg quinupristin/dalfopristin (30:70 ratio) disk should provide the following zone diameter with the indicated quality control strain.

Microorganism (ATCC®  #)	Zone Diameter Range (mm)
Staphylococcus aureus (25923)	21 to 28

ATCC® is a registered trademark of the American Type Culture Collection

INDICATIONS AND USAGE

Synercid is indicated in adults for the treatment of the following infections when caused by susceptible strains of the designated microorganisms.

Complicated skin and skin structure infections caused by Staphylococcus aureus (methicillin susceptible) or Streptococcus pyogenes. (See CLINICAL STUDIES.)

CONTRAINDICATIONS

Synercid is contraindicated in patients with known hypersensitivity to Synercid, or with prior hypersensitivity to other streptogramins (e.g., pristinamycin or virginiamycin).

WARNINGS

Drug Interactions

In vitro drug interaction studies have demonstrated that Synercid significantly inhibits cytochrome P450 3A4 metabolism of cyclosporin A, midazolam, nifedipine and terfenadine. In addition, 24 subjects given Synercid 7.5 mg/kg q8h for 2 days and 300 mg of cyclosporine on day 3 showed an increase of 63% in the AUC of cyclosporine, an increase of 30% in the Cmax of cyclosporine, a 77% increase in the t1/2 of cyclosporine, and, a decrease of 34% in the clearance of cyclosporine. Therapeutic level monitoring of cyclosporine should be performed when cyclosporine must be used concomitantly with Synercid.

It is reasonable to expect that the concomitant administration of Synercid and other drugs primarily metabolized by the cytochrome P450 3A4 enzyme system may likely result in increased plasma concentrations of these drugs that could increase or prolong their therapeutic effect and/or increase adverse reactions. (See Table below.) Therefore, coadministration of Synercid with drugs which are cytochrome P450 3A4 substrates and possess a narrow therapeutic window requires caution and monitoring of these drugs (e.g., cyclosporine), whenever possible. Concomitant medications metabolized by the cytochrome P450 3A4 enzyme system that may prolong the QTc interval should be avoided.

Concomitant administration of Synercid and nifedipine (repeated oral doses) and midazolam (intravenous bolus dose) in healthy volunteers led to elevated plasma concentrations of these drugs. The Cmax increased by 18% and 14% (median values) and the AUC increased by 44% and 33% for nifedipine and midazolam, respectively.

Table of Selected Drugs That Are Predicted to Have Plasma Concentrations Increased by Synercid +

Antihistamines: astemizole, terfenadine

Anti-HIV (NNRTIs and Protease inhibitors): delavirdine, nevirapine, indinavir, ritonavir

Antineoplastic agents: vinca alkaloids (e.g., vinblastine), docetaxel, paclitaxel

Benzodiazepines: midazolam, diazepam

Calcium channel blockers: dihydropyridines (e.g., nifedipine), verapamil, diltiazem

Cholesterol-lowering agents: HMG-CoA reductase inhibitors (e.g., lovastatin)

GI motility agents: cisapride

Immunosuppressive agents: cyclosporine, tacrolimus

Steroids: methylprednisolone

Other: carbamazepine, quinidine, lidocaine, disopyramide

+ This list of drugs is not all inclusive.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Synercid, and may range in severity from mild diarrhea to fatal colitis.  Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD.  Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.  CDAD must be considered in all patients who present with diarrhea following antibiotic use.  Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

PRECAUTIONS

General

Venous Irritation: Following completion of a peripheral infusion, the vein should be flushed with 5% Dextrose in Water solution to minimize venous irritation. DO NOT FLUSH with saline or heparin after Synercid administration because of incompatibility concerns.

If moderate to severe venous irritation occurs following peripheral administration of Synercid diluted in 250 mL of Dextrose 5% in water, consideration should be given to increasing the infusion volume to 500 or 750 mL, changing the infusion site, or infusing by a peripherally inserted central catheter (PICC) or a central venous catheter. In clinical trials, concomitant administration of hydrocortisone or diphenhydramine did not appear to alleviate venous pain or inflammation.

Rate of Infusion

In animal studies toxicity was higher when Synercid was administered as a bolus compared to slow infusion. However, the safety of an intravenous bolus of Synercid has not been studied in humans. Clinical trial experience has been exclusively with an intravenous duration of 60 minutes and, thus, other infusion rates cannot be recommended.

Arthralgias/Myalgias

Episodes of arthralgia and myalgia, some severe, have been reported in patients treated with Synercid. In some patients, improvement has been noted with a reduction in dose frequency to q12h. In those patients available for follow-up, treatment discontinuation has been followed by resolution of symptoms. The etiology of these myalgias and arthralgias is under investigation.

Superinfections

The use of antibiotics may promote the overgrowth of nonsusceptible organisms. Should superinfection occur during therapy, appropriate measures should be taken.

Hyperbilirubinemia

Elevations of total bilirubin greater than 5 times the upper limit of normal were noted in approximately 25% of patients in the non-comparative studies. (See ADVERSE REACTIONS: Non-Comparative Trials.) In some patients, isolated hyperbilirubinemia (primarily conjugated) can occur during treatment, possibly resulting from competition between Synercid and bilirubin for excretion. Of note, in the comparative trials, elevations in ALT and AST occurred at a similar frequency in both the Synercid and comparator groups.

Information for Patients

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

Drug Interactions

In vitro drug interaction studies have shown that Synercid significantly inhibits cytochrome P450 3A4. (See WARNINGS.)

Synercid does not significantly inhibit human cytochrome P450 1A2, 2A6, 2C9, 2C19, 2D6, or 2E1. Therefore, clinical interactions with drugs metabolized by these cytochrome P450 isoenzymes are not expected.

A drug interaction between Synercid and digoxin cannot be excluded but is unlikely to occur via CYP3A4 enzyme inhibition. Synercid has shown in vitro activity (MICs of 0.25 mcg/mL when tested on two strains) against Eubacterium lentum. Digoxin is metabolized in part by bacteria in the gut and as such, a drug interaction based on Synercid's inhibition of digoxin's gut metabolism (by Eubacterium lentum) may be possible.

In vitro combination testing of Synercid with aztreonam, cefotaxime, ciprofloxacin, and gentamicin, against Enterobacteriaceae and Pseudomonas aeruginosa did not show antagonism.

In vitro combination testing of Synercid with prototype drugs of the following classes: aminoglycosides (gentamicin), β-lactams (cefepime, ampicillin, and amoxicillin), glycopeptides (vancomycin), quinolones (ciprofloxacin), tetracyclines (doxycycline) and also chloramphenicol against enterococci and staphylococci did not show antagonism.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies in animals have not been conducted with Synercid. Five genetic toxicity tests were performed. Synercid, dalfopristin, and quinupristin were tested in the bacterial reverse mutation assay, the Chinese hamster ovary cell HGPRT gene mutation assay, the unscheduled DNA synthesis assay in rat hepatocytes, the Chinese hamster ovary cell chromosome aberration assay, and the mouse micronucleus assay in bone marrow. Dalfopristin was associated with the production of structural chromosome aberrations when tested in the Chinese hamster ovary cell chromosome aberration assay. Synercid and quinupristin were negative in this assay. Synercid, dalfopristin, and quinupristin were all negative in the other four genetic toxicity assays.

No impairment of fertility or perinatal/postnatal development was observed in rats at doses up to 12 to 18 mg/kg (approximately 0.3 to 0.4 times the human dose based on body-surface area).

Pregnancy

Teratogenic Effects:Pregnancy Category B: Reproductive studies have been performed in mice at doses up to 40 mg/kg/day (approximately half the human dose based on body-surface area), in rats at doses up to 120 mg/kg/day (approximately 2.5 times the human dose based on body-surface area), and in rabbits at doses up to 12 mg/kg/day (approximately half the human dose based on body-surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to Synercid.

There are, however, no adequate and well-controlled studies with Synercid in pregnant women. Because animal reproduction studies are not always predictive of the human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

In lactating rats, Synercid was excreted in milk. It is not known whether Synercid is excreted in human breast milk. Because many drugs are excreted in human milk, caution should be exercised when Synercid is administered to a nursing woman.

Hepatic Insufficiency

Following a single 1-hour infusion of Synercid (7.5 mg/kg) to patients with hepatic insufficiency, plasma concentrations were significantly increased. (See CLINICAL PHARMACOLOGY: Special Populations.) However, the effect of dose reduction or increase in dosing interval on the pharmacokinetics of Synercid in these patients has not been studied. Therefore, no recommendations can be made at this time regarding the appropriate dose modification.

Pediatric Use

Synercid has been used in a limited number of pediatric patients under emergency-use conditions at a dose of 7.5 mg/kg q8h or q12h. However, the safety and effectiveness of Synercid in patients under 16 years of age have not been established.

Geriatric Use

In phase 3 comparative trials of Synercid, 37% of patients (n=404) were ≥65 years of age, of which 145 were ≥75 years of age. In the phase 3 non-comparative trials, 29% of patients (n=346) were ≥65 years of age, of which 112 were ≥75 years of age. There were no apparent differences in the frequency, type, or severity of related adverse reactions including cardiovascular events between elderly and younger individuals.

Adverse Reactions

The safety of Synercid was evaluated in 1099 patients enrolled in 5 comparative clinical trials. Additionally, 4 non-comparative clinical trials (3 prospective and 1 retrospective in design) were conducted in which 1199 patients received Synercid for infections due to Gram-positive pathogens for which no other treatment option was available. In non-comparative trials, the patients were severely ill, often with multiple co-morbidities or physiological impairments, and may have been intolerant to or failed other antibacterial therapies.

COMPARATIVE TRIALS

ADVERSE REACTION SUMMARY – ALL COMPARATIVE STUDIES

Safety data are available from five comparative clinical studies (n= 1099 Synercid; n= 1095 comparator). One of the deaths in the comparative studies was assessed as possibly related to Synercid. The most frequent reasons for discontinuation due to drug-related adverse reactions were as follows:

% of patients discontinuing therapy by reaction type

Type	Synercid	Comparator
Venous	9.2	2.0
Non-venous	9.6	4.3
-Rash	1.0	0.5
-Nausea	0.9	0.6
-Vomiting	0.5	0.5
-Pain	0.5	0.0
-Pruritus	0.5	0.3

CLINICAL REACTIONS – ALL COMPARATIVE STUDIES

Adverse reactions with an incidence of ≥1% and possibly or probably related to Synercid administration include:

Adverse Reactions	% of patients with adverse reactions
	Synercid	Comparator
Inflammation at infusion site	42.0	25.0
Pain at infusion site	40.0	23.7
Edema at infusion site	17.3	9.5
Infusion site reaction	13.4	10.1
Nausea	4.6	7.2
Thrombophlebitis	2.4	0.3
Diarrhea	2.7	3.2
Vomiting	2.7	3.8
Rash	2.5	1.4
Headache	1.6	0.9
Pruritus	1.5	1.1
Pain	1.5	0.1

Additional adverse reactions that were possibly or probably related to Synercid with an incidence less than 1% within each body system are listed below:

Body as a Whole: abdominal pain, worsening of underlying illness, allergic reaction, chest pain, fever, infection;

Cardiovascular: palpitation, phlebitis;

Digestive: constipation, dyspepsia, oral moniliasis, pancreatitis, pseudomembranous enterocolitis, stomatitis;

Metabolic: gout, peripheral edema;

Musculoskeletal: arthralgia, myalgia, myasthenia;

Nervous: anxiety, confusion, dizziness, hypertonia, insomnia, leg cramps, paresthesia, vasodilation;

Respiratory: dyspnea, pleural effusion;

Skin and Appendages: maculopapular rash, sweating, urticaria;

Urogenital: hematuria, vaginitis

CLINICAL REACTIONS – SKIN AND SKIN STRUCTURE STUDIES

In two of the five comparative clinical trials Synercid (n=450) and comparator regimens (e.g., oxacillin/vancomycin or cefazolin/vancomycin; n=443) were studied for safety and efficacy in the treatment of complicated skin and skin structure infections. The adverse event profile seen in the Synercid patients in these two studies differed significantly from that seen in the other comparative studies. What follows is safety data from these two studies.

Discontinuation of therapy was most frequently due to the following drug related events:

	% of patients discontinuing therapy by reaction type
Type	Synercid	Comparator
Venous	12.0	2.0
Non-venous	11.8	4.0
-Rash	2.0	0.9
-Nausea	1.1	0.0
-Vomiting	0.9	0.0
-Pain	0.9	0.0
-Pruritus	0.9	0.5

Venous adverse events were seen predominately in patients who had peripheral infusions. The most frequently reported venous and non-venous adverse reactions possibly or probably related to study drug were:

	% of patients with adverse reactions
	Synercid	Comparator
Venous	68.0	32.7
-Pain at infusion site	44.7	17.8
-Inflammation at infusion site	38.2	14.7
-Edema at infusion site	18.0	7.2
-Infusion site reaction	11.6	3.6
Non-venous	24.7	13.1
-Nausea	4.0	2.0
-Vomiting	3.7	1.0
-Rash	3.1	1.3
-Pain	3.1	0.2

There were eight (1.7%) episodes of thrombus or thrombophlebitis in the Synercid arms and none in the comparator arms.

LABORATORY EVENTS-ALL COMPARATIVE STUDIES

The following table shows the number (%) of patients exhibiting laboratory values above or below the clinically relevant “critical” values during treatment phase (with an incidence of 0.1% or greater in either treatment group).

Parameter	Critically High or Low Value	Synercid Critically High or Low	Comparator Critically High or Low
AST	> 10 x ULN	9 (0.9)	2 (0.2)
ALT	> 10 x ULN	4 (0.4)	4 (0.4)
Total Bilirubin	> 5 x ULN	9 (0.9)	2 (0.2)
Conjugated Bilirubin	> 5 x ULN	29 (3.1)	12 (1.3)
LDH	> 5 x ULN	10 (2.6)	8 (2.1)
Alk Phosphatase	> 5 x ULN	3 (0.3)	7 (0.7)
Gamma-GT	> 10 x ULN	19 (1.9)	10 (1.0)
CPK	> 10 x ULN	6 (1.6)	5 (1.4)
Creatinine	≥440 μmoL/L	1 (0.1)	1 (0.1)
BUN	≥35.5 mmoL/L	2 (0.3)	9 (1.2)
Blood Glucose	> 22.2 mmoL/L	11 (1.3)	11 (1.3)
	< 2.2 mmoL/L	1 (0.1)	1 (0.1)
Bicarbonates	> 40 mmoL/L	2 (0.3)	3 (0.5)
	< 10 mmoL/L	3 (0.5)	3 (0.5)
CO2	> 50 mmoL/L	0 (0.0)	0 (0.0)
	< 15 mmoL/L	1 (0.2)	0 (0.0)